PROJECT ABSTRACT The research plan uses Mendelian randomization methods and other genetic and molecular epidemiologic approaches to evaluate the hypothesis that circulating and bioavailable vitamin D levels are associated with decreased colorectal cancer risk and further investigate possible mechanisms for the associations. The Mendelian randomization project will leverage resources from three established epidemiologic consortia, including data from approximately 29,000 cases and 46,000 controls of European, Asian and African descent. Fine-mapping will be conducted to improve the instruments for Mendelian randomization analyses. Race- specific genetic scores for circulating vitamin D and its binding protein will be created and assessed for associations with overall colorectal cancer risk. In addition, data and biological samples obtained from participants of the prospective Southern Community Cohort Study will be used to conduct a molecular epidemiologic study. A subsample of 300 Southern Community Cohort Study participants with available colorectal cancer tumor tissue, will be compared to matched controls to evaluate associations of tumor characteristics with circulating vitamin D levels, bioavailable vitamin D levels, vitamin D binding protein levels, and genetic scores composed of vitamin D loci. Tumor characteristics to be examined represent underlying cellular processes associated with carcinogenesis such as cellular proliferation, differentiation, inflammation and apoptosis. We will measure PIK3CA mutation status, tumor stage, and expression of COX-2, p53, and Ki67. The use of Mendelian randomization and molecular epidemiologic methods should provide a more definitive answer to the questions of the relations between colorectal cancer risk and vitamin D binding protein, genetic loci and circulating and bioavailable vitamin D. The findings from this research project will be used to develop and submit a R01-level project before the completion of the Career Development award. The research topic is of much significance, as the Institute of Medicine?s 2010 Report states, understanding the effect of genetic variation in vitamin D status on health outcomes, including that among racial groups, is an important research need. This study will provide insight into colorectal cancer etiology and potentially identify subgroups of individuals who may benefit the most from vitamin D supplementation.